title: Eukaryotic elongation factor 2 kinase regulates the development of hypertension through oxidative stress-dependent vascular inflammation.
abstract: Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca2+/calmodulin-dependent protein kinase. We recently demonstrated that eEF2K protein increases in mesenteric artery from spontaneously hypertensive rats (SHR). Pathogenesis of hypertension is regulated in part by vascular inflammation. We tested the hypothesis whether eEF2K mediates vascular inflammatory responses and development of hypertension. In vascular endothelial cells, small interfering RNA (siRNA) against eEF2K inhibited induction of VCAM-1 and endothelial-selectin as well as monocyte adhesion by TNF-α (10 ng/ml). eEF2K siRNA inhibited phosphorylation of JNK and NF-κB p65 as well as reactive oxygen species (ROS) production by TNF-α. In vascular smooth muscle cells, eEF2K siRNA also inhibited VCAM-1 induction and phosphorylation of JNK and NF-κB by TNF-α. In vivo, increased blood pressure in SHR and ROS production, induction of inflammatory molecules, and hypertrophy in SHR superior mesenteric artery were reduced by an eEF2K inhibitor NH125 (500 μg·kg(-1)·day(-1)). In SHR superior mesenteric artery, impairment of ACh-induced relaxation was normalized by NH125. The present results for the first time demonstrate that eEF2K mediates TNF-α-induced vascular inflammation via ROS-dependent mechanism, which is at least partly responsible for the development of hypertension in SHR.
authors.affiliation: Laboratory of Veterinary Pharmacology, School of Veterinary Medicine, Kitasato University, Towada, Aomori, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Usui
authors.forename: Muneyoshi
authors.initials: M
authors.lastname: Okada
authors.forename: Yukio
authors.initials: Y
authors.lastname: Hara
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yamawaki
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D054736:Elongation Factor 2 Kinase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects* / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014657:Vasculitis / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D007093:Imidazoles; D016328:NF-kappa B; C414024:NH 125; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C517689:EEF2K protein, human; C517691:Eef2k protein, rat; D054736:Elongation Factor 2 Kinase; D048670:MAP Kinase Kinase 4
keywords: hypertension; inflammation; reactive oxygen species; signal transduction; vasoconstriction